Ion Channel Drug Discovery In Vitro Assays

Ion channels are membrane proteins that allow ions to pass through. Establishing a resting membrane potential, creating action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume are all functions of these proteins. Ion channels are usually assembled from several individual proteins. A circular arrangement of similar or homologous proteins firmly packed around a water-filled pore through the plane of the membrane or lipid bilayer is typical of such "multi-subunit" assemblies. The pore-forming subunit(s) of most voltage-gated ion channels is referred to as the α subunit, whereas the auxiliary subunits are referred to β, γ, and so on.

Pharmacology

Ion channel medications have long been utilized to treat a variety of disorders, particularly those affecting electrically excitable tissues. The therapeutic usefulness of several basic medicines that target ion channels has been established thanks to the identification of ion channelopathies.

• Ion channel blockers

Tetrodotoxin (TTX): blocks sodium channels.
Saxitoxin: blocks voltage-dependent sodium channels.
The local anesthetics Lidocaine and Novocaine: inhibit sodium ion channels.
Dendrotoxin: inhibits potassium channels.
Iberiotoxin: blocks potassium channels.
Heteropodatoxin: shuts off potassium channels.

• Ion channel activators

Calcium channel openers, like Bay K8644.
Chloride channel openers, like phenanthroline.
Potassium channel openers, like minoxidil.
Sodium channel openers, like DDT.

Feature and Classification

Ion channels are found inside the membranes of many intracellular organelles as well as all excitable cells. They are frequently compared to being likened to little water-filled tunnels that only allow ions of a certain size and charge to pass through. This property is known as selective permeability. The typical channel pore is only one or two atoms wide at its narrowest point and is selective for specific ion species, such as sodium or potassium. Some channels may permit the flow of multiple types of ions, frequently with a shared charge. Ions commonly pass through the channel pore segments in a single stream, almost as quickly as they do through the free solution. A "gate," which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force, regulates passage through the pore in many ion channels. Ion permeation and gating are two fundamental properties of ion channels. The passage of ions via an open channel is referred to as ion permeation. Ion channels are classified based on their selective permeability to specific ions (e.g., Na⁺, K⁺, and Ca²⁺ channels). Size, valency, and hydration energy are important determinants of selectivity.

Fig.1. Ion channel. (Zhou, 2001)

Reference

1. Zhou, Y.; et al. Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 Å resolution. Nature. 2001, 414(6859): 43-48.